Recent experiments have shown that old assumptions about the equal contributions of the maternal and paternal genomes are incorrect and that for important genes, only one of the parental alleles is normally expressed. This phenomenon is called genomic imprinting because one of the parental alleles has presumably been marked by a biochemical imprint. Imprinting may account for the fact that some genetic diseases may occur more often if the gene is inherited from the father than from the mother or vice versa. Not only is imprinting required for normal development, but the failure of the imprinting process for some genes may lead to a proclivity for oncogenesis. Imprinted genes are frequently involved in the regulation of cell growth. Thus, it is likely that alterations in the imprinting process may lead to aberrant growth and development. Imprinting is a plastic phenomenon which demonstrates promoter, tissue, and developmental specificities. The Specific Aims of this grant are as follows: 1. Our goal is to understand the mechanisms underlying the coordinate yet reciprocal imprinting of the contiguous insulin-like growth factor-II (Igf2) and H19 genes in normal tissues and during development. To this end, we have developed a model based on our discovery of a putative imprinting maintenance element upstream of Igf2 which regulates both Igf2 and H19 imprinting. We plan to test this model using in vitro as well as in vivo transgenic systems. 2. To understand the plasticity of the imprinting process, we have chosen to study Igf2, a gene which is imprinted in a promoter-specific, tissue-specific, and development-specific manner. We will compare Igf2 expression in the central nervous system, a tissue which uniquely expresses Igf2 biallelically from all four promoters, with its expression from other tissues in which it is always imprinted. In particular, we will examine how DNA methylation, histone acetylation and antisense regulate the expression of this imprinted gene.